Circulatory shock and hypovolemic shock are commonly occurring threatening pathophysiological states, which can occur secondary to trauma, hemorrhage, burns, sepsis, allergic reactions, and heart failure. Shock-like microcirculatory abnormalities are also associated with certain procedures, such as surgical procedures. Such shock, whether systemic or localized, is characterized by a reduction in blood pressure, blood flow, and/or blood volume, and can cause an insufficient supply of blood and oxygen to vital organs and tissues. This insufficient blood and oxygen supply can cause local hypoxia, ischemia, and can lead to loss of cellular and organ function and even death.
Currently-available treatments for circulatory and hypovolemic shock include forms of volume infusion. For example, the standard of care in initial management of hemorrhagic shock is rapid administration of large volumes fluids, several liters in an adult patient. A preferred fluid is Ringer's lactate, although normal saline or other similar isotonic crystalloid solutions are also used. The standard continued treatment is based on an observed response to the initial fluid therapy. Guidelines generally provide that up to 300 ml of electrolyte solution is required for each 100 ml of blood lost (“three for one” rule). For blood losses up to 30% of circulation blood volume, crystalloid alone will often suffice; however, with ongoing blood loss, or a more significant hemorrhage, prompt surgical intervention or blood therapy becomes necessary.
Over the last decade, this standard approach has been reexamined, leading to the conclusion that changes are needed in current resuscitation strategies used by first responders to trauma settings and by medical personnel in emergency rooms (ER) and intensive care units (ICU). There are multiple reasons for this conclusion.
First, the clinical trajectory of patients who develop multiple organ failure is set early in the resuscitation process (i.e., within about 6 hr of an event that creates a risk of shock, such as an injury resulting in hemorrhaging). Many patients at high risk require emergency surgery or interventional radiology, and arrive in an ICU after this time window. Although resuscitation efforts in the ICU can clearly modify the subsequent clinical course for the patient, even highly refined and individually tailored resuscitation cannot reverse the dysfunctional response that has already occurred. As such, currently-used resuscitation strategies do not adequately limit the incidence of multiple organ failure.
Second, although initial crystalloid volume loading is valuable in defining hemodynamic stability, to continue this process in the face of ongoing hemorrhaging promotes further bleeding, hemodilutes the patient, and sets the stage for hypothermia, acidosis, and coagulopathy. This syndrome is particularly problematic in patients with blunt trauma, who often have sources of bleeding that are not amenable to direct control. Failure to resuscitate these patients will, however, ultimately lead to irreversible shock. As such, currently used resuscitation strategies can actually exacerbate ischemic injury.
Third, although crystalloid resuscitation is efficacious in most patients, it produces problematic tissue edema in patients who arrive to an ICU in severe shock. These patients typically need massive fluid resuscitation to maintain intravascular volume and many develop abdominal compartment syndrome, which creates increased risks for multiple organ failure. Patients with severe torso trauma who are admitted with shock and an associated severe closed head injury are in a precarious situation. Under-resuscitation decreases cerebral perfusion pressure, which causes secondary brain injury. Excessive crystalloid administration promotes cerebral edema, which increases intracranial pressure and further decrease cerebral perfusion pressure. As such, currently used resuscitation strategies can exacerbate injury.
Fourth, shock initiates dysfunctional inflammation that causes multiple organ failure. Resuscitation is an obligatory intervention to decrease the severity of the shock insult, but current strategy is not directed at modulating inflammation, in fact, it may worsen it. Laboratory studies show that lactated Ringer's solution activates neutrophils. Even more disturbing is an observation that blood transfusion contains proinflammatory mediators that both prime and activate neutrophils. As such, currently used resuscitation strategies can exacerbate injury.
Prospective randomized controlled trials studying currently-used resuscitation strategies (crystalloid and colloid resuscitation) were conducted in the 1970s and 1980s, before the recognition of abdominal compartment syndrome as an important clinical entity. Additionally, albumin was the principal colloid used, but other types of colloid, such as starches and gelatins, are available and are now being used in resuscitation. Because of their higher molecular weights, colloids such as starches and gelatins are confined to the intravascular space, and their infusion results in more efficient plasma volume expansion. In severe hemorrhagic shock, however, the permeability of capillary membranes increases, allowing colloids to enter the interstitial space, which can then worsen edema and impair tissue oxygenation. Although it has been suggested that these high-molecular-weight agents could plug capillary leaks that occur during neutrophil-mediated organ injury, it has not been established that such a benefit could result from their use.
It has also been proposed that resuscitation with albumin induces renal failure and even impairs pulmonary function. Similarly, hetastarch has been shown to induce renal dysfunction in patients with septic shock and in recipients of kidneys from brain-dead donors. Hetastarch also has a limited role in massive resuscitation because it causes a coagulopathy and hyperchloremic acidosis due to its high chloride content. A new hydroxyethyl starch (HES) preparation (e.g., HEXTEND®) purportedly does not cause these adverse effects, but has not been studied in massive resuscitation. It is now thought that colloids might reduce the incidence of abdominal compartment syndrome, but this possible benefit must be weighed against the potentially detrimental effects of colloids already reported.
Results of numerous studies indicate that HES administration can lead to reduction in circulating factor VII and von Willebrand factor levels, impairment of platelet function, prolongation of partial thromboplastin time and activated partial thromboplastin time, and increase in bleeding complications. Coagulopathy and hemorrhage associated with HES are often encountered in cardiac surgery, a setting in which susceptibility to such complications is heightened by transient acquired platelet dysfunction resulting from the procedure. Thus, in cardiac surgery studies with albumin as the control, HES has resulted in platelet depletion and dysfunction, prothrombin time and activated partial thromboplastin time prolongation, and increased postoperative bleeding. Dextran, as compared with albumin, has been shown to reduce platelets and increase postoperative bleeding in cardiac surgery patients. Postoperative blood loss was early correlated with the volume of gelatin used to prime the extracorporeal circuit. Artificial colloids, including dextran, hetastarch and pentastarch, have been associated with renal impairment, and HES has been demonstrated to increase sensitive markers of renal tubule damage in surgical patients. In a study of sepsis patients, HES exposure was recently shown to be an independent risk factor for acute renal failure. In the renal transplantation setting, HES has been found to reduce urinary output, increase creatinine levels and dopamine requirement, and increase the need for hemodialysis or hemodiafiltration.
Studies have suggested that both over- and under-resuscitation can increase mortality. Early aggressive fluid resuscitation can be deleterious, according to a clinical trail in which mortality was reduced by delaying fluid therapy. Also, there are several practical and logistic limitations to the current methods of prehospital resuscitation, which include limitations on the amount of fluid that can be delivered due to inadequate i.v. bore size and limited availability of fluid in the field, e.g. combat casualty care. Hypotensive resuscitation is one approach that has been advocated as a better means to perform field resuscitation of penetrating trauma. However, early application of aggressive resuscitation has been shown to affect outcomes deleteriously in animal models of uncontrolled hemorrhage, in which aggressive resuscitation using a variety of fluids caused rapid increases in blood pressure, internal bleeding, and higher mortality.
In the early 1980s research interest in hypertonic saline was spurred. Small-volume hypertonic saline was shown to be as effective as large-volume crystalloids in expanding plasma volume and enhancing cardiac output in hemorrhagic shock in animals. Furthermore, hypertonic saline increased perfusion of the microcirculation, presumably by selective arteriolar vasodilation and by decreasing swelling of red blood cells and of the endothelium. This improved microcirculation, however, could lead to increased bleeding. Consequently, hypertonic saline was tested in animal models of uncontrolled hemorrhagic shock and was shown to increase bleeding, but mortality was model-dependent and the best survival was obtained when saline was given with high-volume crystalloids. Additionally, the resuscitative effectiveness of hypertonic saline was found to be enhanced by combination with dextran (hypertonic saline dextran (HSD)). In view of the small volume needed to achieve these effects, there was great interest in the use of these fluids in resuscitation in the field for both military and civilian use.
From the late 1980s through the early 1990s, several trials were done. Individually, these trials found survival outcome to be inconsistently improved, but did document that a bolus of hypertonic saline or HSD was safe. Meta-analysis of these data suggests that hypertonic saline is no better than standard of care isotonic crystalloid fluids, but that HSD might be better. Subgroup analysis showed that patients who presented with shock and concomitant severe closed head injury benefited most from HSD. This observation was consistent with laboratory data showing that, compared with isotonic crystalloid, hypertonic saline or HSD increases cerebral perfusion pressure, decreases intracranial pressure, and decreases brain edema, in combined head injury and hemorrhagic shock. This finding has led some authorities to recommend that hypertonic saline should replace mannitol in the management of intracranial hypertension in patients with severe closed head injury. The argument in favor of hypertonic saline is even more compelling with the recent recognition that hypertonic saline resuscitation decreases the inflammatory response (specifically neutrophil cytotoxicity) in animal models of hemorrhagic shock, ischemia and reperfusion, and sepsis.
More recent studies have compared hypotensive and normotensive resuscitation of hemorrhage using lactated Ringer's (LR) with hypotensive resuscitation using HEXTEND® (Hex) 6% hetastarch in isotonic buffered saline in a multi-hemorrhage sheep model. Hypotensive resuscitation with LR greatly reduced volume requirements as compared with normotensive resuscitation, and Hex achieved additional volume sparing. However, trends toward lower base excess (BE) values and low levels of urinary flow in some animals in both hypotensive treatment protocols and the occurrence of deaths only in the hypotensive treatment protocols suggest that resuscitation to a target MAP of 65 mmHg may be too low for optimal outcomes. Hypotensive resuscitation regimens may reduce bleeding but do not optimally restore metabolic function.
To summarize, currently-available treatments for circulatory and hypovolemic shock focus on various forms of volume infusion. Intravenous fluids appear to improve hemodynamic indices in the short term, but most also have adverse consequences on hemostatic mechanisms. Indeed, it is now becoming clear that resuscitation fluids may actually potentiate cellular injury via severe immune activation and upregulation of cellular injury markers that can result in exacerbation of blood loss. Bleeding can also be enhanced by injudicious fluid administration as a consequence of dilutional coagulopathy and secondary clot disruption from increased blood flow, increased perfusion pressure, and decreased blood viscosity.
Accordingly, there remains a need in the art for a method of treating circulatory and hypovolemic shock, which avoids the above-identified problems.